Project Summary This is a 4-year renewal for a multi-generation, 30-year longitudinal study of families at high- and low-risk for Major Depressive Disorder (MDD). The project has yielded important findings on the familial transmission of mood disorders and has contributed to the field's understanding of the long-term temporal sequences of disorders from childhood to adulthood, as well as the neurobiological correlates of these processes. However, despite these advances, the mechanisms through which familial risk leads to offspring impairment remains underdeveloped. NIMH's Research Domain Criteria (RDoC) offers a compelling model for testing potential mechanisms, by proposing functional systems (?constructs?) that combine neurobiological and behavioral information. This renewal therefore aims to prospectively test whether RDoC constructs are mechanisms (i.e., mediators) through which family history leads to adult functional outcomes and symptom trajectories. Leveraging a rich, 30-year, 3-generation longitudinal dataset, we will integrate data from multiple units of analysis (multiple MRI modalities, electrophysiology, behavior, and self-report) to define latent variables corresponding to 3 latent RDoC constructs: Acute Threat, Approach Motivation, and Response Inhibition. First, we will quantify the test-retest reliability of our RDoC indicators (MRI, physiology, behavior, etc.) by re-assessing each of these indicators in a representative subsample of participants (Aim 1). This is an important first step as it will afford robust modeling of the latent RDoC constructs and bolster the premise that the RDoC constructs are trait-like (i.e., stable) mechanisms of familial transmission. Second, we will use structural equation modeling to create the 3 RDoC constructs from these indicators and their reliability estimates. We will then prospectively examine whether the 3 latent RDoC constructs instantiate mechanisms by which family history of MDD leads to negative outcomes in adulthood (Aim 2). Third, we will leverage our multigenerational dataset to examine the inter-generational transmission of the RDoC constructs. We will test the incremental validity of the RDoC constructs over DSM defined psychopathology by examining whether their familial transmission is independent of the familial transmission of MDD (Aim 3). In sum, this renewal application advances this multi-generation study toward a focus on mechanisms of risk ? a critical step to developing novel interventions to prevent negative adulthood outcomes associated with familial depression. In addition to our Specific Aims, this renewal will also afford the opportunity to furnish the data from this unique study (i.e., many thousands of clinical and neurobiological data points collected from families from 1982? present) onto the NIH RDoC repository, making this 30-year longitudinal dataset available to the entire scientific community.